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Effect of Rotigotine Vs Placebo on Cognitive Functions Among Patients with Mild to Moderate Alzheimer Disease a Randomized Clinical Trial

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Effect of Rotigotine Vs Placebo on Cognitive Functions Among Patients with Mild to Moderate Alzheimer Disease a Randomized Clinical Trial Original Investigation | Neurology Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease A Randomized Clinical Trial Giacomo Koch, MD, PhD; Caterina Motta, MD; Sonia Bonnì, PhD; Maria Concetta Pellicciari, PhD; Silvia Picazio, Psy, PhD; Elias Paolo Casula, PhD; Michele Maiella, MSc; Francesco Di Lorenzo, MD; Viviana Ponzo, BSc; Clarissa Ferrari, PhD; Eugenia Scaricamazza, MD; Carlo Caltagirone, MD; Alessandro Martorana, MD Abstract Key Points Question Can 24 weeks of treatment IMPORTANCE Impairment of dopaminergic transmission may contribute to cognitive dysfunction with rotigotine modify cognitive in Alzheimer disease (AD). functions in patients with mild to moderate Alzheimer disease? OBJECTIVE To investigate whether therapy with dopaminergic agonists may affect cognitive functions in patients with AD. Findings In this randomized clinical trial including 94 participants, 24 weeks of DESIGN, SETTING, AND PARTICIPANTS This phase 2, monocentric, randomized, double-blind, rotigotine treatment did not placebo-controlled trial was conducted in Italy. Patients with mild to moderate AD were enrolled significantly modify global cognition; between September 1, 2017, and December 31, 2018. Data were analyzed from July 1 to September however, the treatment did improve 1, 2019. frontal lobe functions and was efficacious in reducing functional INTERVENTIONS A rotigotine 2 mg transdermal patch for 1 week followed by a 4 mg patch for 23 impairment compared with placebo. weeks (n = 47) or a placebo transdermal patch for 24 weeks (n = 47). Meaning These findings suggest that rotigotine may be useful for improving MAIN OUTCOMES AND MEASURES The primary end point was change from baseline on the frontal cognitive functions and activities Alzheimer Disease Assessment Scale–Cognitive Subscale. Secondary end points were changes in of daily living in patients with mild to Frontal Assessment Battery, Alzheimer Disease Cooperative Study–Activities of Daily Living, and moderate Alzheimer disease. Neuropsychiatric Inventory scores. Prefrontal cortex activity was evaluated by transcranial magnetic stimulation combined with electroencephalography. + Visual Abstract RESULTS Among 94 patients randomized (mean [SD] age, 73.9 [5.6] years; 58 [62%] women), 78 + Supplemental content (83%) completed the study. Rotigotine, as compared with placebo, had no significant effect on the Author affiliations and article information are primary end point: estimated mean change in Alzheimer Disease Assessment Scale–Cognitive listed at the end of this article. Subscale score was 2.92 (95% CI, 2.51-3.33) for the rotigotine group and 2.66 (95% CI, 2.31-3.01) for the placebo group. For the secondary outcomes, there were significant estimated mean changes between groups for Alzheimer Disease Cooperative Study–Activities of Daily Living score (−3.32 [95% CI, −4.02 to −2.62] for rotigotine and −7.24 [95% CI, −7.84 to −6.64] for placebo) and Frontal Assessment Battery score (0.48 [95% CI, 0.31 to 0.65] for rotigotine and −0.66 [95% CI, −0.80 to −0.52] for placebo). There was no longitudinal change in Neuropsychiatric Inventory scores (1.64 [95% CI, 1.06-2.22] for rotigotine and 1.26 [95% CI, 0.77-1.75] for placebo group). Neurophysiological analysis of electroencephalography results indicated that prefrontal cortical activity increased in rotigotine but not in the placebo group. Adverse events were more common in the rotigotine group, with 11 patients dropping out compared with 5 in the placebo group. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, rotigotine treatment did not significantly affect global cognition in patients with mild to moderate AD; however, improvement (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(7):e2010372. doi:10.1001/jamanetworkopen.2020.10372 (Reprinted) July 15, 2020 1/12 Downloaded From: https://jamanetwork.com/ by a University College London User on 07/31/2020 JAMA Network Open | Neurology Effect of Rotigotine on Cognitive Functions Among Patients With Alzheimer Disease Abstract (continued) was observed in cognitive functions highly associated with the frontal lobe and in activities of daily living. These findings suggest that treatment with the dopaminergic agonist rotigotine may reduce symptoms associated with frontal lobe cognitive dysfunction and thus may delay the impairment of activities of daily living. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03250741 JAMA Network Open. 2020;3(7):e2010372. doi:10.1001/jamanetworkopen.2020.10372 Introduction In the last decades, much evidence has strengthened the idea that the impairment of dopaminergic transmission may contribute to cognitive dysfunction in Alzheimer disease.1-3 Dopamine is a key neuromodulator affecting several distinct steps of synaptic transmission, playing an important role in the control of high cognitive functions, such as memory, learning, and decision-making. Postmortem studies have revealed marked loss of dopamine receptors in the temporal and frontal lobes of brains with Alzheimer disease, suggesting an association between decreased levels of D2-like receptor and Alzheimer disease pathophysiology.4,5 These neuropathological findings were confirmed by in vivo investigations with positron emission tomography.6 Some early attempts have been carried out using dopaminergic drugs, such as L-dopa7 or selegiline,8 in samples of patients with Alzheimer disease at different stages of the disease, with some controversial results. More recently, experimental studies in animal models of Alzheimer disease showed that dopaminergic agonists may reduce amyloid deposition and improve memory9,10 and that the degeneration of dopaminergic neurons in the ventral tegmental area contributes to memory deficits.11 It has also been shown that in the early stages of Alzheimer disease, dopaminergic agonists improve cholinergic transmission12 and cortical plasticity13 likely by acting on the dopaminergic projections over the frontal cortex.1 Taken together, this evidence provides novel implications for therapies based on dopaminergic stimulation in patients with mild to moderate Alzheimer disease. Hence, we hypothesized that therapy with dopaminergic agonists could have a relevant clinical effect on cognitive impairment in patients with Alzheimer disease. We performed a trial to evaluate the efficacy and safety of the dopaminergic agonist rotigotine as adjunctive therapy to standard treatment with acetylcholinesterase inhibitors in patients with mild to moderate Alzheimer disease. Methods Study Design Patients were eligible for this phase-2 randomized clinical trial if they had an established diagnosis of probable Alzheimer disease according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria; were aged 50 to 85 years; had a Clinical Dementia Rating14 score of 0.5 to 1 (scores range from 0 to 3, with higher scores indicating worse dementia) and Mini Mental State Examination (MMSE) score of 18 to 26 at screening (scores range from 0 to 30), indicating mild to moderate Alzheimer disease; had 1 caregiver; had been treated with acetylcholinesterase inhibitor for at least 6 months; and had undergone a lumbar puncture for cerebrospinal fluid biomarkers analysis for diagnostic purposes.15 Patients underwent medical and neurologic evaluations, including magnetic resonance imaging or computed tomography. Patients were excluded if they had extrapyramidal signs, history of stroke, another neurodegenerative disorder, psychotic disorders, or if they had been treated within 6 months before enrollment with antipsychotic, antiparkinsonian, anticholinergic, or antiepileptic drugs. The trial was approved by the review board and ethics committee at Santa Lucia Foundation JAMA Network Open. 2020;3(7):e2010372. doi:10.1001/jamanetworkopen.2020.10372 (Reprinted) July 15, 2020 2/12 Downloaded From: https://jamanetwork.com/ by a University College London User on 07/31/2020 JAMA Network Open | Neurology Effect of Rotigotine on Cognitive Functions Among Patients With Alzheimer Disease and was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All patients or their legal representatives provided written informed consent. Patients could withdraw at any point without prejudice. This report followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized studies. Randomization and Masking This was a monocentric, randomized, double-blind trial of rotigotine vs placebo in patients with mild to moderate Alzheimer disease as an add-on to treatment with acetylcholinesterase inhibitors. The trial protocol is available in Supplement 1. The trial comprised a 24-week treatment period with 1 week of dose escalation of transdermal patches of rotigotine at 2 mg per day and 23 weeks of dose maintenance of transdermal patches of rotigotine at 4 mg per day. The dose of rotigotine used in the trial was recommended by an independent data and safety monitoring committee, whose members reviewed data from a safety evaluation and identified the maximum safe dose not associated with unacceptable adverse effects.16 A low 4-mg dosage was chosen because such a drug has been previously found to be effective in modulating cholinergic activity and cortical plasticity
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